1. Field of the Invention
The present invention relates to novel processes for producing aspartyl dipeptide ester derivatives, which are useful as sweeteners.
2. Discussion of the Background
In recent years, as eating habits have been improved to a high level, obesity caused by excessive sugar intake and the diseases accompanied by obesity have become a serious health issue. Accordingly, the development of low-calorie sweeteners (sweetening agent) that replace sugar has been strongly in demand. As a sweetener that is widely used at present, there is aspartame which is excellent in safety and quality of sweetness, but however, is somewhat problematic in stability.
Against this background, certain N-[N-(phenylpropyl having various and specified substituent group(s) on the benzene ring)-L-xcex1-aspartyl]-L-phenylalanine 1-methyl esters (aspartame derivatives) have been found to be sweeteners which are excellent in stability and, moreover, are better by far in degree of sweetness, i.e., have an advantage in cost per degree of sweet taste, (see, International Patent Publication WO99/52937). However, no method for the efficient process for production of these sweeteners is, as yet, known.
N-[N-(3-phenylpropyl)-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester and N-[N-(3-methoxy-4-hydroxyphenylpropyl)-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester, which are poor in a degree (potency) of sweetness as compared to these compounds, are described in the International Patent Publication WO94/11391. However, in this publication, no examples which would show a suitable operation for the synthesis thereof including the starting material employed is provided, and there is no mention of any process for the production of these compounds.
Meanwhile, a process which comprises reductively alkylating aspartame with a 3-(phenyl having various substituent group(s) on the benzene ring)-2-propenyl aldehyde and hydrogen in the presence of a catalyst has been proposed by some of the present inventors and the like for production of the above-mentioned aspartame derivatives which are useful as sweeteners (see, Japanese Patent Application No. 11-287398 and International No. PCT/JP00/06626 description). However, there remains a need for a process which affords these compounds with a further improvement in yield.
Accordingly, it is one object of the present invention to provide novel processes for the production of N-[N-(phenylpropyl having various and specified substituent group(s) on the benzene ring)-L-xcex1-aspartyl]-L-phenylalanine 1-methyl esters (aspartame derivatives) which are useful as sweeteners and which yields these compounds in an improved yield.
In particular, it is another object of the present invention to provide novel processes which afford improved yields of the compounds of formula (2): 
wherein in formula (2) R1, R2, R3, R4 and R5 are each independently of each other a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms, and a hydroxyalkyloxy group having 2 or 3 carbon atoms, wherein two symbols of R1 and R2, or two symbols of R2 and R3 may be combined together to denote a methylenedioxy group.
It is another object of the present invention to provide an efficient and industrial process for producing such compounds.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that N-[N-(phenylpropyl having various and specified substituent group(s) on the benzene ring)-L-xcex1-aspartyl]-L-phenylalanine 1-methyl esters (aspartame derivatives), more specifically aspartyl dipeptide ester derivatives represented by the general formula (2): 
wherein in formula (2) R1, R2, R3, R4 and R5 are each independently of each other a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms, and a hydroxyalkyloxy group having 2 or 3 carbon atoms, wherein two symbols of R1 and R2, or two symbols of R2 and R3 may be combined together to denote a methylenedioxy group,
can be easily produced by reductively alkylating aspartame in the presence of a base and a catalyst, with an aldehyde represented by the following general formula (1) and hydrogen: 
wherein in formula (1), R1, R2, R3, R4 and R5 are each independently of each other a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms, a benzyloxy group and a hydroxyalkyloxy group having 2 or 3 carbon atoms, wherein two symbols of R1 and R2, or two symbols of R2 and R3 may be combined together to denote a methylenedioxy group, and the hydroxyl group (xe2x80x94OH) may denote a substituent group (xe2x80x94OM; M=metal atom) in its derivative form where the hydrogen atom in said hydroxyl group has been replaced by a metal atom,
and where necessary neutralizing the product with an acid.
That is, the present invention provides the following embodiments and aspects:
(1) A process for producing an aspartyl dipeptide ester derivative represented by the following general formula (2): 
wherein in formula (2) R1, R2, R3, R4 and R5 are each independently of each other a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms, and a hydroxyalkyloxy group having 2 or 3 carbon atoms, wherein two symbols of R1 and R2, or two symbols of R2 and R3 may be combined together to denote a methylenedioxy group,
which comprises:
reductively alkylating aspartame with an aldehyde represented by the following general formula (1), and hydrogen in the presence of a catalyst and a base: 
wherein in formula (1), R1, R2, R3, R4 and R5 are each independently of each other a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms, a benzyloxy group and a hydroxyalkyloxy group having 2 or 3 carbon atoms, wherein two symbols of R1 and R2, or two symbols of R2 and R3 may be combined together to denote a methylenedioxy group, and the hydroxyl group (xe2x80x94OH) may denote a substituent group (xe2x80x94OM; M=metal atom) in its derivative form where the hydrogen atom in said hydroxyl group has been replaced by a metal atom.
Said derivative of formula (2) may be in any form of the free form and the salt form.
Accordingly, the object compound can be produced and obtained in the salt form through the reductive alkylation reaction. Where necessary or desired, the salt form may be further converted into the free form, whereby the object compound can be produced and obtained. Any such form of the object compound and any such process therefor are contained in the present invention. To the present invention, in addition to the reductive alkylation reaction process, any usual and conventional process, such as a salt-formation process, a desalination process, and/or a purification process may be added so long as the object thereof is not inhibited or impaired.
Incidentally, in the case when the aldehyde of formula (1) used as the starting material contains a benzyloxy group, the benzyloxy group is converted into a hydroxyl group by the removal of the benzyl group in the benzyloxy moiety, and thereby the object compound of formula (2) obtained after the reaction does not contain a benzyloxy group, and instead contains a hydroxyl group.
(2) The process (1) as defined above, wherein said derivative of formula (2) obtained as the object compound is in the free form.
In this case, the process includes a process for converting said derivative existing in the salt form obtained in the reductive alkylation reaction into that in the free form.
(3) The process (1) or (2) as defined above, wherein in said general formula (1), R1, R2, R3, R4 and R5 are each independently of each other a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, a methoxy group, a methyl group and a benzyloxy group, and in said general formula (2), R1, R2, R3, R4 and R5 are each independently of each other a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, a methoxy group and a methyl group.
(4) The process as defined in the process (1) to (3), wherein in the above process, the aldehyde of formula (1) used as the starting material has a hydroxyl group on the benzene ring or the like, and at least one part (a portion) of hydrogen atoms in the hydroxyl groups of the aldehyde molecules has been replaced by a metal atom, and at least one part (a portion) of the aldehyde molecules wherein the hydroxyl group has been converted into metal alkoxide, is present as said base.
In the present invention, in the case when the aldehyde contains a hydroxyl group, and the hydroxyl group is converted to metal alkoxide, the aldehyde can also serve as all or a portion of the base. Therefore, in this case, the use of an additional base is not necessary. Moreover, the use of a surplus or excess of base is not preferred since a secondary reaction arises.
(5) The process as defined above, wherein in said formulae (1) and (2), R1 is a hydrogen atom, a methyl group or a hydroxyl group, R2 is a hydrogen atom, a methyl group or a hydroxyl group, R3 is a methoxy group, and R4 and R5 are a hydrogen atom. In this process, in the aldehyde of formula (1), at least one of R1 and R2 may be a benzyloxy group. In particular, the process as defined above, particularly the process (1) to (4), wherein in the above formulae, R2 is a hydrogen atom or a hydroxyl group, R3 is a methoxy group, and R1, R4 and R5 are a hydrogen atom, is preferred. Among them, the process as defined above, particularly the process (1) to (4), wherein in the above formulae, R1, R4 and R5 are a hydrogen atom, R2 is a hydroxyl group, R3 is a methoxy group, is more preferred.
(6) The process as defined above, wherein in said formulae (1) and (2), R1 is a hydrogen atom, a methyl group or a methoxy group, R2 is a hydrogen atom, a methyl group or a methoxy group, R3 is a hydroxyl group, and R4 and R5 are a hydrogen atom, and in the formula (1), R3 may be a benzyloxy group. In particular, the process as defined above, particularly the process (1) to (4), wherein in the above formulae, R2 is a hydrogen atom or a methoxy group, R3 is a hydroxyl group, and R1, R4 and R5 are a hydrogen atom, is preferred.
(7) The process as defined above, particularly the process (1) to (3), wherein said base is at least one selected from the group consisting of metal hydrides, metal alcoxides (alkoxides), metal hydroxides, and amines.
(8) The process (7) as defined above, wherein said metal hydride is selected from the group consisting of LiH, NaH, KH and the like, said metal alkoxide is selected from the group consisting of LiOMe, NaOMe, KOMe and the like, said metal hydroxide is selected from the group consisting of LiOH, NaOH, KOH, Mg(OH)2 and the like, and said base is at least one of these compounds.
(9) The process (7) as defined above, wherein said amine is at least one of Et3N and Et2NH.
(10) The process as defined above, particularly the process (1) to (3), wherein said base is sodium hydroxide or potassium hydroxide.
(11) The process as defined above, particularly the process (1) to (3), which comprises a process for mixing said base with said aldehyde previously, i.e., prior to the addition of the aspartame.
(12) The process as defined above, particularly the process (1) to (4), wherein said aldehyde is a compound represented by the following general formula (3) or (4); or
which comprises a process for conversion of a corresponding aldehyde into a compound represented by the following general formula (3) or (4): 
In the above formulae (3) and (4), X denotes any one of lithium atom, sodium atom and potassium atom. Me denotes a methyl group.
In this process, since the aldehyde can also concurrently serve as the base, in the reductive alkylation reaction with the aspartame, the use of an additional base (new base) is not necessary.
(13) The process as defined above, particularly the process (1) to (4), wherein said base is any one of a lithium compound, a sodium compound and/or a potassium compound, and the above described aldehyde is a compound represented by the following general formula (3xe2x80x2) or (4xe2x80x2), and which comprises a process for mixing said aldehyde with said base previously (i.e., prior to the addition of the aspartame) to form a salt represented by the following general formula (3) or (4); 
In the above formulae (3) and (4), X denotes any one of lithium atom, sodium atom and/or potassium atom. Me denotes a methyl group.
In this process, as in the one described immediately above, since the aldehyde can also concurrently serve as the base, in the reductive alkylation reaction with the aspartame, the use of an additional base is not necessary.
(14) The process as defined above, particularly the process (1) to (4), which comprises a process for converting the derivative of formula (2) existing in the salt form obtained in said reductive alkylation reaction, into said derivative existing in the free form through neutralization with an acid.
(15) The process (14) as defined above, wherein said acid is any one of hydrochloric acid, sulfuric acid, and/or acetic acid.
(16) The process (14) as defined above, wherein in said reductive alkylation reaction, the neutralization with an acid is conducted during a hydrogenation reaction.
(17) The process as defined above, particularly the process (1) to (4), wherein in said reductive alkylation reaction, the temperature for the hydrogenation reaction is in a range of 0 to 60xc2x0 C.
(18) The process as defined above, particularly the process (1) to (4), which comprises in said reductive alkylation reaction, a process for retaining the reaction mixture while stirring for at least 10 minutes at a temperature of 40xc2x0 C. or lower before the hydrogenation reaction.
(19) The process as defined above, particularly the process (1) to (4), which comprises in said reductive alkylation reaction, a process for removing at least one portion of any water contained in the solvent before the hydrogenation reaction.
(20) The process as defined above, particularly the process (1) to (4), wherein said catalyst is a catalyst for hydrogenation, and is at least one of palladium on carbon, palladium black, Raney Nickel, and/or platinum on carbon.
(21) The process as defined above, particularly the process (1) to (4), wherein said reaction is conducted in a solvent.
(22) The process (21) as defined above, wherein said solvent is alcohol, particularly methanol, or a mixed solvent of methanol with other solvent(s) (water-containing methanol and the like).
(23) The process as defined above, particularly the process (1) to (4), which comprises in said reductive alkylation reaction, a hydrogenation reaction with a hydrogen pressure of 0.1 to 10 MPa, preferably 0.1 to 1.0 MPa.
(24) The process as defined above, particularly the process (1) to (4), wherein the above described derivative of formula (2) as the object compound exists in the free form, and which comprises a process for crystallization of said derivative with a mixed solvent of water-alcohol after the process for production of the free form.
Through the crystallization process, the salt can be removed efficiently for purification.
(25) The process (24) as defined above, wherein the alcohol used for the above described solvent for crystallization (the mixed solvent) is a methanol.